Lymph node contraction links sex-biased naive CD8 T cell decline to compromised antigen recognition

The numerical abundance of diverse naive CD8 T cell clones is essential to provide broad protection against infection and cancer. Here, we uncover a sex-biased mechanism of immune aging in which age-related thymic involution limits naive CD8 T cell supply, while male mice exhibit an additional early depletion of naive CD8 T cells driven by accelerated, antigen-agnostic differentiation into virtual memory cells. This combined loss leads to contraction of lymph nodes and reduced local naive T cell clone availability, limiting antigen recognition capacity. Therapeutic thymus regeneration via androgen ablation repopulates naive CD8 T cells in lymph nodes and reinvigorates tumor recognition in middle-aged male mice. These findings reveal the crucial impact of sex and age on locoregional naive T cell clone abundance in lymph nodes and suggest strategies to restore immune competence in aging males.